Hyaluronate Compositions

ABSTRACT

The present invention provides compositions suitable for topical administration to a mammalian subject including sodium hyaluronate and a pharmaceutically acceptable excipient. The present invention also provides methods for making and using the same.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/022,095, filed Jan. 29, 2008, now U.S. Pat. No. 8,466,128, whichclaims the benefit of U.S. Provisional Patent Application No.60/898,297, filed on Jan. 30, 2007, the contents of both of which arehereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to compositions and methods for treating skindisorders, and for maintaining or enhancing the moisture of skin. Inparticular, the invention relates to compositions that containhyaluronic acid and/or its salt as an active ingredient, and methods ofusing and making the same.

BACKGROUND OF THE INVENTION

Typically, for the treatment of skin diseases such as xerosis senilisand miliaria, adrenocortical steroid-based agents, urea-based ointments,heparinoids from animal organs, or vaselin-based ointments such asazulene ointments, have been used. However, most of these agents haveundesirable side effects. For example, the adrenocortical steroid-basedagents are likely to cause various side effects. The urea-basedointments sometimes cause irritation or smarting. The heparinoids fromanimal organs sometimes cause a contact dermatitis as a side effect. Onthe other hand, the vaselin-based ointments such as azulene ointmentspresent unpleasant sticky feeling. In addition, dusts are likely todeposit on vaselin-based ointments. Thus, there have been no satisfyingtreatment agents for skin diseases.

SUMMARY OF THE INVENTION

The present invention provides improved compositions and methods fortreating skin disorders or for maintaining or enhancing the moisture ofskin. The compositions and methods of the present invention have bettertherapeutic effects and are safer and pleasant to use.

Thus, in one aspect, the present invention provides a compositionsuitable for topical administration to a mammalian subject (e.g., human)that contains sodium hyaluronate. In some embodiments, the compositionincludes, by mass, from about 0.05% to about 5% sodium hyaluronate and apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutically acceptable excipient is predominantly in the liquidphase at ambient temperature. In certain embodiments, from about 0.001wt % to about 5 wt % of the sodium hyaluronate in the composition has amolecular weight ranging between about 0.01 megadaltons and about 0.4megadaltons. In certain embodiments, from about 0.001 wt % to about 5 wt% of the sodium hyaluronate in the composition has a molecular weightranging between about 0.5 megadaltons and about 1.6 megadaltons. Incertain embodiments, from about 50 wt % to about 95 wt % of the sodiumhyaluronate in the composition has a molecular weight ranging betweenabout 1.7 megadaltons and about 4.0 megadaltons. As used in thisapplication, “wt %” or “%” represents weight/weight percentage. “wt %”and “%” are used interchangeably herein.

In one embodiment, the present invention provides a composition suitablefor topical administration to a mammalian subject (e.g., human)including, by mass, from about 0.05% to about 5% sodium hyaluronate anda pharmaceutically acceptable excipient, wherein from about 0.001 wt %to about 5 wt % of the sodium hyaluronate in the composition has amolecular weight ranging between about 0.01 megadaltons and about 0.4megadaltons, from about 0.001 wt % to about 5 wt % of the sodiumhyaluronate in the composition has a molecular weight ranging betweenabout 0.5 megadaltons and about 1.6 megadaltons, from about 50 wt % toabout 95 wt % of the sodium hyaluronate in the composition has amolecular weight ranging between about 1.7 megadaltons and about 4.0megadaltons, and wherein the pharmaceutically acceptable excipient ispredominantly in the liquid phase at ambient temperature. As usedherein, “1 megadalton” equals 1 million Daltons (i.e., 1,000,000daltons).

In some embodiments, the pharmaceutically acceptable excipient suitablefor the present invention is selected from the group consisting ofwater, an alcohol, an oil, glycerin, polyethylene glycol, lanolin,petrolatum, wax, and poloxamer.

In certain embodiments, the pharmaceutically acceptable excipient is analcohol. In certain embodiments, the pharmaceutically acceptableexcipient is an alcohol selected from the group consisting of ethanol,benzyl alcohol, isopropyl alcohol, octyldodecanol, cetostearyl alcohol,and lanolin alcohol.

In certain embodiments, the pharmaceutically acceptable excipient is anoil. In certain embodiments, the pharmaceutically acceptable excipientis an oil selected from the group consisting of almond oil, castor oil,corn oil, cottonseed oil, light mineral oil, mineral oil, olive oil,peanut oil, polyoxyl 35 castor oil, sesame oil, soybean oil, andsunflower oil. In some embodiments, the pharmaceutically acceptableexcipient includes white petrolatum.

In certain embodiments, the pharmaceutically acceptable excipient iswater. In certain embodiments, the ratio of the mass of water to thetotal mass of the composition is about 50% or greater, about 55% orgreater, about 60% or greater, about 65% or greater, about 70% orgreater, about 75% or greater, about 80% or greater, about 85% orgreater, about 90% or greater, about 95% or greater, about 96% orgreater, about 97% or greater, about 98% or greater, about 99% orgreater, about 99.5% or greater. In certain embodiments, the ratio ofthe mass of water to the total mass of the composition ranges from about60% to about 99.9%. In certain embodiments, the ratio of the mass ofwater to the total mass of the composition ranges from about 90.0% toabout 99.9%. In certain embodiments, the ratio of the mass of water tothe total mass of the composition ranges from about 92.5% to about99.8%. In certain embodiments, the ratio of the mass of water to thetotal mass of the composition ranges from about 95.0% to about 99.7%. Incertain embodiments, the ratio of the mass of water to the total mass ofthe composition ranges from about 97.5% to about 99.6%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 98.5% to about 99.5%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 99.0% to about 99.4%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 99.2% to about 99.3%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition is about 99.235%.

In some embodiments, the composition further includes an antifungalagent. In certain embodiments, the antifungal agent suitable for theinvention is selected from the group consisting of clioquinol,haloprogin, miconazole nitrate, povidone-iodine, tolnaftate,ketoconazole, undecylenic acid, butoconazole and clotrimazole. In oneembodiment, the antifungal agent suitable for the invention isclotrimazole.

In some embodiments, the composition further includes an antibiotic. Incertain embodiments, the antibiotic suitable for the invention isselected from the group consisting of bacitracin, bacitracin zinc,chlortetracycline hydrochloride, neomycin sulfate, clindamycin,erythromycin, and tetracycline hydrochloride.

In some embodiments, the composition further includes an anti-acneagent. In certain embodiments, the anti-acne agent suitable for theinvention is selected from the group consisting of benzoyl peroxide,resorcinol, resorcinol monoacetate, salicylic acid, sulfur, adapalene,alitretinoin, etretinate, isotretinoin, tazarotene, and tretinoin. Incertain embodiments, the anti-acne agent is benzoyl peroxide. In certainembodiments, the ratio of the mass of benzoyl peroxide to the total massof the composition ranges from about 2.5% to about 10%.

In some embodiments, the composition further includes an antiviralagent. In some embodiments, the composition further includes butylatedhydroxytoluene. In some embodiments, the composition further includesbutylated hydroxyanisole. In some embodiments, the composition includeswhite petrolatum and butylated hydroxytoluene. In certain embodiments,the composition includes white petrolatum and butylated hydroxyanisole.

In certain embodiments, the composition further includes one or moreceramides. In certain embodiments, the composition further includes acorticosteroid. In certain embodiments, the corticosteroid is selectedfrom the group consisting of betamethasone valerate, betamethasonedipropionate, dexamethasone acetate, dexamethasone sodium phosphate,hydrocortisone, hydrocortisone acetate, and hydrocortisone butyrate.

In some embodiments, the composition has an apparent viscosity of fromabout 5,000 to about 300,000 centipoise. In some embodiments, thecomposition has an apparent viscosity of from about 10,000 to about300,000 centipoise. In some embodiments, the composition has an apparentviscosity of from about 10,000 to about 20,000 centipoise.

In some embodiments, the pH of the composition ranges from about 4 toabout 8.

In another aspect, the present invention provides a composition suitablefor maintaining or enhancing the moisture of skin. In some embodiments,the composition includes, by mass, at least about 80% water; sodiumhyaluronate; one or more preservatives; one or more thickening agents;and one or more bases; wherein the ratio of the mass of sodiumhyaluronate to the total mass of the composition is about 0.05%, 0.1%,0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5%. In oneembodiment, the ratio of the mass of sodium hyaluronate to the totalmass of the composition is about 0.1%.

In some embodiments, the sodium hyaluronate has a molecular weightbetween about 1.6 million Daltons (i.e., 1.6 megadaltons) and about 2.8million Daltons (i.e., 2.8 megadaltons).

In some embodiments, the one or more preservatives suitable for theinvention are selected from the group consisting of methylparaben,propylparaben, edetate sodium, benzalkonium chloride, and benzylalcohol. In certain embodiments, the one or more preservatives includemethylparaben. In certain embodiments, the one or more preservativesinclude propylparaben. In certain embodiments, the one or morepreservatives include methylparaben and propylparaben.

In some embodiments, the one or more thickening agents suitable for theinvention are selected from the group consisting of carbomer 940, methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, polyvinyl alcohol, one or more alginates, acacia, and one ormore chitosans. In certain embodiments, the one or more thickeningagents include carbomer 940.

In some embodiments, the one or more bases suitable for the inventionare selected from the group consisting of trolamine, sodium hydroxide,sodium bicarbonate, potassium hydroxide, magnesium hydroxide, calciumhydroxide, ammonium hydroxide, and potassium bicarbonate. In certainembodiments, the one or more bases include trolamine.

In some embodiments, the pH of the composition is between about 4 andabout 8.

In some embodiments, the composition has an absorbance of not more than0.1 at 600 nm and a path of 1.0 cm. In some embodiments, the compositionhas a viscosity measured at temperature of 25 degree Celsius of not lessthan 5,000 centipoise and not more than 100,000 centipoise. In someembodiments, the composition has an absorbance of not more than 0.1 at600 nm and a path of 1.0 cm and a viscosity measured at temperature of25 degree Celsius of not less than 5,000 centipoise and not more than100,000 centipoise.

In yet another aspect, the present invention provides a compositionsuitable for maintaining or enhancing the moisture of skin, including,by mass, at least about 90% water; sodium hyaluronate; methylparaben;propylparaben; carbomer 940; and trolamine, wherein the ratio of themass of sodium hyaluronate to the total mass of the composition is about0.05% to 0.3%.

In some embodiments, the sodium hyaluronate has a molecular weightbetween about 1.6 million Daltons (i.e., 1.6 megadaltons) and about 2.8million Daltons (i.e., 2.8 megadaltons).

In still another aspect, the present invention provides a compositionsuitable for maintaining or enhancing the moisture of skin, including,by mass, at least about 95% water; 0.1% sodium hyaluronate; one or morepreservatives; one or more thickening agents; and one or more bases;wherein the composition has an absorbance of not more than 0.1 at 600 nmand a path of 1.0 cm and wherein the composition has a viscositymeasured at temperature of 25 degree Celsius of not less than 5,000centipoise and not more than 300,000 centipoise. In some embodiments,the composition of the invention has a viscosity measured at temperatureof 25 degree Celsius of not less than 10,000 centipoise and not morethan 200,000 centipoise. In some embodiments, the composition of theinvention has a viscosity measured at temperature of 25 degree Celsiusof not less than 10,000 centipoise and not more than 20,000 centipoise.In some embodiments, the composition of the invention has a viscositymeasured at temperature of 25 degree Celsius of not less than 11,000centipoise and not more than 18,000 centipoise. In some embodiments, thesodium hyaluronate has a molecular weight between about 1.6 millionDaltons and about 2.8 million Daltons.

In a further aspect, the present invention provides a compositionsuitable for maintaining or enhancing the moisture of skin, consistingessentially of, by mass, at least about 99% water; about 0.1% sodiumhyaluronate; one or more preservatives; one or more thickening agents;and one or more bases.

In some embodiments, the sodium hyaluronate has a molecular weightbetween about 1.6 million Daltons and about 2.8 million Daltons.

In still another aspect, the present invention provides a compositionsuitable for maintaining or enhancing the moisture of skin, consistingessentially of, by mass, about 0.1% sodium hyaluronate, about 0.2%methylparaben, about 0.02% propylparaben, about 0.3% carbomer 940, about0.15% trolamine, and about 99.23% water.

In some embodiments, the sodium hyaluronate has a molecular weightbetween about 1.6 million Daltons and about 2.8 million Daltons.

Combinations of various embodiments described above are within the scopethe invention. The present invention further encompasses the use of thecomposition as described in various embodiments above in skin disordertherapy. The present invention also encompasses the use of thecomposition of as described in various embodiments above for themanufacture of a medicament for the treatment of skin disorder.

Thus, in one aspect, the present invention provides a method fortreating a skin disorder on a mammalian subject (e.g., human). In someembodiments, the method includes administering to a subject an effectiveamount of the composition of the present invention, in particular, asdescribed in various embodiments above.

In some embodiments, the present invention can be used to treat a skindisorder selected from the group consisting of eczema, dermatitis,atopic dermatitis, xerosis, psoriasis, inflammation, diaper rash, fungalinfection and acne.

In some embodiments, the composition is administered at least once perday. In some embodiments, the composition is administered at least twiceper day. In some embodiments, the composition is administered threetimes per day.

In another aspect, the present invention provides a process formanufacturing a composition of the invention. In some embodiments, theprocess includes the steps of: (a) admixing one or more preservatives,sodium hyaluronate, and one or more thickening agents to form apre-water mixture; (b) admixing one or more bases and water to form awater mixture; (c) admixing the pre-water mixture and the water mixtureto form a post-water mixture; and (d) homogenizing the post-watermixture to form the composition.

In some embodiments, step (a) includes admixing methylparaben,propylparaben, sodium hyaluronate, and carbomer 940 in an approximateratio, by mass, of 0.2:0.02:0.1:0.3 to form the pre-water mixture.

In some embodiments, step (b) includes admixing trolamine and water inan approximate ratio, by mass, of 0.15:99.23 to form the water mixture.

In some embodiments, step (c) includes admixing the pre-water mixtureand the water mixture in an approximate ratio, by mass, of 0.62:99.38,to form a post-water mixture.

In this application, the use of “or” means “and/or” unless statedotherwise. As used in this application, the term “comprise” andvariations of the term, such as “comprising” and “comprises,” are notintended to exclude other additives, components, integers or steps. Asused in this application, the terms “about” and “approximately” are usedas equivalents. Any numerals used in this application with or withoutabout/approximately are meant to cover any normal fluctuationsappreciated by one of ordinary skill in the relevant art.

Other features, objects, and advantages of the present invention areapparent in the detailed description that follows. It should beunderstood, however, that the detailed description, while indicatingembodiments of the present invention, is given by way of illustrationonly, not limitation. Various changes and modifications within the scopeof the invention will become apparent to those skilled in the art fromthe detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides improved compositions and methods fortreating skin disorders or for maintaining or enhancing the moisture ofskin. A composition according to the invention includes hyaluronic acidor its salt (e.g., sodium hyaluronate) as an active ingredient and oneor more pharmaceutically acceptable excipients. In particular, acomposition according to the invention may contain a very highproportion of water by mass. As a result, the composition of theinvention is not only therapeutically effective in treating skindisorders, but also has certain consumer-appealing characteristics, suchas clarity and suitable viscosity, over the course of time, and lackscertain unappealing characteristics, such as greasiness.

Various aspects of the invention are described in detail in thefollowing sections. The use of sections is not meant to limit theinvention. Each section can apply to any aspect of the invention. Inthis application, the use of “or” means “and/or” unless statedotherwise.

Hyaluronic Acid and its Salt

The source of the hyaluronate used in the present invention may be ahyaluronic acid or any acceptable salt form of hyaluronic acid. As usedherein, the term “hyaluronate” means hyaluronic acid and itsequivalents, which includes hyaluronic acid of varying molecular weightsand any of their salt forms, such as sodium hyaluronate.

Hyaluronic acid is a linear mucopolysaccharide comprised of alternatingglucuronic acid and N-acetyl-glucosamine residues that interact withother proteoglycans to provide stability and elasticity to theextracellular matrix of all tissues. This network of macromoleculesregulates tissue hydration and the movement of substances within theinterstitial compartment.

Hyaluronic acid may be used in the form of an acid, or in the form of ahyaluronic acid salt. Suitable salt form includes, but is not limitedto, an alkali metal salt such as a sodium or potassium salt, an alkalineearth metal salt such as a magnesium or calcium salt. In particular, asodium salt, i.e., sodium hyaluronate is used in the present invention.

Hyaluronic acid can be obtained from an extract of, for example, acockscomb, a viterous body or an umbilical code, or from a culture ofcertain bacteria such as a hyaluronic acid-producing microorganism ofGenus streptcoccus. Hyaluronic acid can be used for the presentinvention irrespective of its origin. In some embodiments, hyaluronicacid used for the present invention can be obtained from the culture ofa hyaluronic acid-producing microorganism. High molecular weight andhigh purity hyaluronic acid and its salt forms can be obtained usingthis method.

Methods of obtaining highly-pure or ultra-pure hyaluronic acid and itssalt forms, isolation techniques, and analytical methods for testingpurity are provided, for example, in the U.S. Pat. Nos. 3,396,081,4,141,973, 4,517,295, 4,736,024, 4,784,900 and 4,808,576, the teachingsof which are hereby incorporated by reference.

It is contemplated that sodium hyaluronate from any of a number ofsources may be used as a starting material in making a compositionaccording to the invention. For example, Proturon™ Standard-C sodiumhyaluronate-2222200 from FMC Biopolymer (1735 Market Street,Philadelphia, Pa. 19103) may be used as a starting material.

A composition of the invention may contain sodium hyaluronate at variousconcentrations. Typically, a suitable concentration of sodiumhyaluronate in the composition ranges from, by mass, about 0.001 wt % to5.0 wt %. In certain embodiments, a suitable concentration of sodiumhyaluronate in the composition ranges from, by mass, about 0.05 wt % to5.0 wt %. In certain embodiments, a suitable concentration of sodiumhyaluronate in the composition ranges from, by mass, about 0.05 wt % to0.3 wt %. In certain embodiments, a suitable concentration of sodiumhyaluronate in the composition ranges from, by mass, about 0.05 wt % to1.5 wt %. In certain embodiments, a suitable concentration of sodiumhyaluronate in the composition is about 0.1 wt %.

Typically, sodium hyaluronate suitable for the invention may have amolecular weight ranging between about 10,000 daltons and 8,000,000daltons, or higher. In particular, suitable sodium hyaluronate has amolecular weight ranging between about 10,000 daltons and 400,000daltons; between about 500,000 daltons and 1,600,000 daltons; betweenabout 1,700,000 daltons and 4,000,000 daltons; between about 1,600,000daltons and 2,800,000 daltons; between about 800,000 daltons and4,000,000 daltons; or between about 1,000,000 daltons and 3,000,000daltons.

Without wishing to be bound by any theory, it is contemplated that thephysicochemical and/or physiological properties of sodium hyaluronatevary according to the molecular weight of the molecule. For example, thephysicochemical properties of sodium hyaluronate having a molecularweight of, for example, ten thousand Daltons, differ appreciably fromthe physicochemical properties of sodium hyaluronate having a molecularweight of four million Daltons. Also, the physiological properties ofsodium hyaluronate having a molecular weight of, for example, tenthousand Daltons, differ appreciably from the physiological propertiesof sodium hyaluronate having a molecular weight of four million Daltons.Without wishing to be bound by any theory, it is also contemplated thatsodium hyaluronate having a small molecular weight provides lessmoisturizing effect, and sodium hyaluronate having a molecular weight of4,000,000 daltons or larger tends to be highly viscous, wherebyformulation will be difficult.

Thus, it is desirable to provide a composition that include a blend ofsodium hyaluronate of various molecular weights, given the largevariation in physicochemical and physiological properties of sodiumhyaluronate of differing molecular weights. For example, a compositionaccording to the invention may include a blend of sodium hyaluronatewith one or more combinations of the following: from about 0.001 wt % toabout 5 wt % of the sodium hyaluronate in the composition has amolecular weight of between about 0.01 and about 0.4 megadaltons; and/orfrom about 0.001 wt % to about 5 wt % of the sodium hyaluronate in thecomposition has a molecular weight of between about 0.5 megadaltons andabout 1.6 megadaltons; and/or from about 50 wt % to about 95 wt % of thesodium hyaluronate in the composition has a molecular weight of betweenabout 1.7 megadaltons and about 4.0 megadaltons. As used herein, “wt %”or “%” is weight/weight percentage.

Formulations

A composition of the present invention may be formulated into variousforms. For example, the composition of the invention may be formulatedinto a lotion, an aqueous solution, an emulsifiable ointment, or awater-soluble ointment. It may be formulated in accordance with variousformulation methods known in the art.

Typically, a composition of the invention is clear and suitably viscous.As used in connection with the invention, “clear” refers to the qualityof having an absorbance of not more than 0.1 at 600 nm, where absorbanceis measured at a temperature of 22.5±3.5 degrees Celsius (in otherwords, at any temperature not less than 19.0 degrees Celsius and notmore than 26.0 degrees Celsius), and where the path length is 1.0 cm. Asused herein, the term “absorbance” refers to a measure of the proportionof light absorbed and/or scattered by a fluid, and typically measured ina spectrophotometer. Typically, absorbance refers to the base tenlogarithm of the ratio of the light intensity transmitted by a liquidwater reference sample (or “blank”) to the light intensity transmittedby the sample under analysis, which in this case is a sample of acomposition according to the invention. Purified water USP is used as ablank in this instance.

As used in connection with the invention, “suitably viscous” refers tothe quality of having a viscosity, measured at a temperature of 25degrees Celsius, of not less than 5,000 centipoise and not more than300,000 centipoise. For example, a suitable viscousity includes aviscosity, measured at a temperature of 25 degrees Celsius, ranging fromabout 5, 000 to about 300,000 centipoise, from about 5,000 to about200,000 centipoise, from about 5,000 to about 100,000 centipoise, fromabout 10,000 to about 200,000 centipoise, from about 10,000 to about100,000 centipoise, from about 10,000 to about 20,000 centipoise, orfrom about 11,000 to about 18,000 centipoise. As used herein, the term“viscosity” refers to a measure of the internal friction of a fluid, andtypically measured in a viscometer. Typically, viscosity is the ratio ofshear stress (measured in dynes per square centimeter) to shear rate(measured in reciprocal seconds). A poise, which is equal to 100centipoise, equals one dyne-second per square centimeter.

As used in connection with the invention, “lotion” refers to acomposition useful for application to one or more areas of skin of ahuman subject in order to maintain and/or enhance the moisture of theone or more areas of skin. As used herein, the term “application” refersto contacting the composition with the one or more areas of skin and mayinclude spreading the composition across the one or more areas of skinand/or rubbing the composition into the one or more areas of skin.

Analytical methods used in connection with the invention are those knownin the pharmaceutical arts.

Typically, in addition to active ingredient, hyaluronic acid or its saltform, a suitable formulation of the invention may include one or morepharmaceutically acceptable exicipients, preservatives, thickeningagents, bases, moisturizing agents, antifungal agents, antibiotics,anti-acne agents, stabilizing agents, or other components commonly usedfor treating skin diseases or maintaining or enhancing the moisture ofskin.

Typically, a composition of the invention includes a pharmaceuticallyacceptable excipient. In particular, a pharmaceutically acceptableexcipient suitable for the invention is predominantly in the liquidphase at ambient temperature. Exemplary excipients suitable for theinvention include, but are not limited to, water, alcohol, oil,glycerin, polyethylene glycol, lanolin, petrolatum, wax, and poloxamer.

In certain embodiments, a pharmaceutically acceptable excipient is analcohol. Suitable alcohols include, but are not limited to, ethanol,benzyl alcohol, isopropyl alcohol, octyldodecanol, cetostearyl alcohol,and lanolin alcohol.

In certain embodiments, a pharmaceutically acceptable excipient is oil.Suitable oils include, but are not limited to, almond oil, castor oil,corn oil, cottonseed oil, light mineral oil, mineral oil, olive oil,peanut oil, polyoxyl 35 castor oil, sesame oil, soybean oil, andsunflower oil.

In some embodiments, a pharmaceutically acceptable excipient may includewhite petrolatum.

In some embodiments, a pharmaceutically acceptable excipient is water.Typically, a composition of the invention contains a high percentage ofwater. For example, the ratio of the mass of water to the total mass ofthe composition may be about 50% or greater, about 55% or greater, about60% or greater, about 65% or greater, about 70% or greater, about 75% orgreater, about 80% or greater, about 85% or greater, about 90% orgreater, about 95% or greater, about 96% or greater, about 97% orgreater, about 98% or greater, about 99% or greater, about 99.5% orgreater. In certain embodiments, the ratio of the mass of water to thetotal mass of the composition may range from about 60% to about 99.9%.In certain embodiments, the ratio of the mass of water to the total massof the composition ranges from about 90.0% to about 99.9%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 92.5% to about 99.8%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 95.0% to about 99.7%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 97.5% to about 99.6%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 98.5% to about 99.5%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 99.0% to about 99.4%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition ranges from about 99.2% to about 99.3%. In certainembodiments, the ratio of the mass of water to the total mass of thecomposition is about 99.235%.

Typically, a composition of the invention may contain one or morepreservatives. Suitable preservatives for the invention include, but arenot limited to, methylparaben, propylparaben, edetate sodium,benzalkonium chloride, and benzyl alcohol. Generally, any preservativesknown in the art can be used for the invention.

A composition of the invention may contain one or more thickeningagents. Suitable thickening agents for the invention include, but arenot limited to, carbomer 940, methyl cellulose, xanthan gum,carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, oneor more alginates, acacia, and/or one or more chitosans. Generally, anythickening agents known in the art can be used for the invention.

A composition of the invention may contain one or more bases. Suitablebases include, but are not limited to, trolamine, sodium hydroxide,sodium bicarbonate, potassium hydroxide, magnesium hydroxide, calciumhydroxide, ammonium hydroxide, and potassium bicarbonate. Generally, anybases known in the art can be used for the invention.

A composition of the invention may include an antifungal agent. Suitableantifungal agents include, but are not limited to, clioquinol,haloprogin, miconazole nitrate, povidone-iodine, tolnaftate,ketoconazole, undecylenic acid, butoconazole and clotrimazole. In oneembodiment, the antifungal agent suitable for the invention isclotrimazole.

A composition of the invention may include an antibiotic. Suitableantibiotics include, but are not limited to, bacitracin, bacitracinzinc, chlortetracycline hydrochloride, neomycin sulfate, clindamycin,erythromycin, and tetracycline hydrochloride.

A composition of the invention may include an anti-acne agent. Suitableanti-acne agents include, but are not limited to, benzoyl peroxide,resorcinol, resorcinol monoacetate, salicylic acid, sulfur, adapalene,alitretinoin, etretinate, isotretinoin, tazarotene, and tretinoin. Incertain embodiments, the anti-acne agent is benzoyl peroxide. Anti-acneagents, such as benzoyl peroxide, can be included at variousconcentrations. For example, the ratio of the mass of benzoyl peroxideto the total mass of the composition may range from about 2.5% to about10%.

A composition of the invention may include an antiviral agent. Suitableantiviral agents include, but are not limited to, butylatedhydroxytoluene, butylated hydroxyanisole, butylated hydroxytoluene.

A composition of the invention may include one or more ceramides.Suitable ceramides include, but are not limited to, Types I to VII,N-oleoyl-sphingosine, N-(12-hydroxyoctadecanoyl)sphingosine,N-(16-hydroxyhexadecanoyl)sphingosine and bovine brain ceramide.

A composition of the invention may include a corticosteroid. Suitablecorticosteroids include, but are not limited to, betamethasone valerate,betamethasone dipropionate, dexamethasone acetate, dexamethasone sodiumphosphate, hydrocortisone, hydrocortisone acetate, and hydrocortisonebutyrate.

Typically, the pH of a composition ranges between about 4 and about 8.For example, the pH of a composition according to the invention can beabout 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about7.0, about 7.2, about 7.5, or about 8.0.

As an example, the invention provides a clear, suitably viscous lotioncomposition consisting essentially of, by mass, at least about 99%water; about 0.1% sodium hyaluronate; one or more preservatives; one ormore thickening agents, and one or more bases. For example, the pH ofthe composition may be between about 4 and about 8.

As another example, a composition according to the invention may consistessentially of one or more preservatives, about 0.1%, by mass, sodiumhyaluronate having molecular weight substantially between about 1.6million and about 2.8 million Daltons, one or more thickening agents,one or more bases, and at least about 99%, by mass, water. Such acomposition is useful as a lotion and is clear and suitably viscous.

As a further example, a composition according to the invention consistedessentially of, by mass, about 0.2% methylparaben NF, about 0.02%propylparaben NF, about 0.1% sodium hyaluronate having molecular weightsubstantially between about 1.6 million and about 2.8 million Daltons,about 0.3% carbomer 940 NF, about 0.15% trolamine NF, and about 99.23%purified water USP. Such a composition was useful as a lotion and wasclear and suitably viscous.

As yet another example, a composition according to the inventionconsists essentially of, by mass, from about 0.01% to about 0.1% edetatedisodium USP, from about 0.01% to about 0.02% benzalkonium chloride NF,from about 0.1% to about 0.5% methylcellulose USP, from about 0.01% toabout 0.3% sodium hydroxide NF, about 0.1% sodium hyaluronate havingmolecular weight substantially between about 1.6 million and about 2.8million Daltons, and purified water USP q.s., wherein the compositionhas a pH of between about 4 and about 8. Such a composition is useful asa lotion and is clear and suitably viscous.

As another example, a composition according to the invention consistsessentially of, by mass, from about 0.02% to about 0.5% sodium benzoateNF, from about 0.1% to about 0.2% potassium sorbate NF, from about 0.2%to about 0.5% xanthan gum NF, from about 0.01% to about 0.3% sodiumphosphate monobasic, about 0.1% sodium hyaluronate having molecularweight substantially between about 1.6 million and about 2.8 millionDaltons, and purified water USP q.s., wherein the composition has a pHof between about 4 and about 8. Such a composition is useful as a lotionand is clear and suitably viscous.

As another example, a composition according to the invention consistsessentially of, by mass, from about 0.01% to about 0.02% benzalkoniumchloride NF, from about 0.01% to about 0.3% benzyl alcohol NF, fromabout 0.2% to about 0.5% hydroxyethylcellulose NF, from about 0.01% toabout 0.3% sodium hydroxide, about 0.1% sodium hyaluronate havingmolecular weight substantially between about 1.6 million and about 2.8million Daltons, and purified water USP q.s., wherein the compositionhas a pH of between about 4 and about 8. Such a composition is useful asa lotion and is clear and suitably viscous.

Manufacturing Processes

Generally, a process for manufacturing a composition according to theinvention includes admixing one or more preservatives, sodiumhyaluronate, and one or more thickening agents to form a pre-watermixture; admixing one or more bases and water to form a water mixture;and admixing the pre-water mixture and the water mixture to form apost-water mixture. In general, the post-water mixture is homogenizeduntil the post-water mixture is clear and suitably viscous. Accordingly,samples of the post-water mixture may be collected, for example, duringits homogenization, and analyzed to determine whether the post-watermixture is clear and suitably viscous. A post-water mixture that isclear and suitably viscous is useful as a lotion.

As one example, a process for manufacturing a composition according tothe invention includes admixing methylparaben, propylparaben, sodiumhyaluronate, and carbomer 940 in the approximate ratio, by mass, of0.2:0.02:0.1:0.3 to form a pre-water mixture; admixing trolamine andwater in the approximate ratio, by mass, of 0.15:99.23 to form a watermixture; and admixing the pre-water mixture and the water mixture in theapproximate ratio, by mass, of 0.62:99.38, to form a post-water mixture.In general the post-water mixture is homogenized until the post-watermixture is clear and suitably viscous. Accordingly, samples of thepost-water mixture may be collected, for example during itshomogenization, and analyzed to determine whether the post-water mixtureis clear and suitably viscous. A post-water mixture that is clear andsuitably viscous is useful as a lotion.

As another example, a process for manufacturing a composition accordingto the invention includes admixing edetate sodium, benzalkoniumchloride, sodium hyaluronate, and methylcellulose in the approximateratio, by mass, of 0.05:0.015:0.1:0.5 to form a pre-water mixture;admixing sodium hydroxide and water in the approximate ratio, by mass,of 0.3:98.9 to form a water mixture; and admixing the pre-water mixtureand the water mixture in the approximate ratio, by mass, of 0.8:99.2, toform a post-water mixture. In general the post-water mixture ishomogenized until the post-water mixture is clear and suitably viscous.Accordingly, samples of the post-water mixture may be collected, forexample during its homogenization, and analyzed to determine whether thepost-water mixture is clear and suitably viscous. A post-water mixturethat is clear and suitably viscous is useful as a lotion.

As yet another example, a process for manufacturing a compositionaccording to the invention includes admixing sodium benzoate, potassiumsorbate, sodium hyaluronate, and xanthan gum in the approximate ratio,by mass, of 0.25:0.15:0.1:0.35 to form a pre-water mixture; admixingsodium phosphate monobasic and water in the approximate ratio, by mass,of 0.15:99 to form a water mixture; and admixing the pre-water mixtureand the water mixture in the approximate ratio, by mass, of 0.85:99.15,to form a post-water mixture. In general the post-water mixture ishomogenized until the post-water mixture is clear and suitably viscous.Accordingly, samples of the post-water mixture may be collected, forexample during its homogenization, and analyzed to determine whether thepost-water mixture is clear and suitably viscous. A post-water mixturethat is clear and suitably viscous is useful as a lotion.

As a further example, a process for manufacturing a compositionaccording to the invention includes admixing benzalkonium chloride,benzyl alcohol, sodium hyaluronate, and hydroxyethylcellulose in theapproximate ratio, by mass, of 0.015:0.15:0.1:0.35 to form a pre-watermixture; admixing sodium hydroxide and water in the approximate ratio,by mass, of 0.15:99.235 to form a water mixture; and admixing thepre-water mixture and the water mixture in the approximate ratio, bymass, of 0.615:99.385, to form a post-water mixture. In general thepost-water mixture is homogenized until the post-water mixture is clearand suitably viscous. Accordingly, samples of the post-water mixture maybe collected, for example during its homogenization, and analyzed todetermine whether the post-water mixture is clear and suitably viscous.A post-water mixture that is clear and suitably viscous is useful as alotion.

A composition according to the invention can also be made according tovarious methods known in the art. For example, components that are inthe liquid phase at ambient temperature may be admixed to form a liquidadmixture, and other components that are in the solid phase at ambienttemperature may be admixed to form a solid admixture. The liquidadmixture and the solid admixture can then admixed to form aliquid-solid admixture. Alternatively, it may be advantageous to firstdissolve some sparingly soluble components, or some which, despite beingvery soluble, are slow to dissolve, in a suitable solvent. By way ofexample and not of limitation, for an aqueous formulation of sodiumhyaluronate, it may be advantageous to admix sodium hyaluronate andwater to form a sodium hyaluronate-water admixture, then add a liquidadmixture and a solid admixture.

A composition according to the invention may be filled into anappropriate dispenser (e.g., a pumper dispenser) or other suitablecontainers by any automated filling equipment suitable for such purposesknown in the art, or by hand, for storage or use.

Treatment of Skin Disorders

The composition of the invention can be used for maintaining orenhancing the moisture of skin. In particular, the composition of theinvention can be used to treat a skin disorder on a mammalian subject,for example, a human patient.

Thus, the present invention provides a method for treating a skindisorder on a mammalian subject by administering to the subject aneffective amount of a composition as described in various embodimentsabove. The composition of the invention may be used to treat a skindisorder including, but not limited to, eczema, dermatitis, atopicdermatitis, xerosis, psoriasis, inflammation, diaper rash, fungalinfection and acne.

Typically, an effective amount is a liberal amount that, whenadministered at regular intervals, is sufficient to treat the skindisease, such as by ameliorating one or more symptoms associated withvarious skin diseases or disorders, for example, scaling, dryness,roughness, redness, sensitiveness, flaking of the skin. The amount whichwill be therapeutically effective for the treatment of the disease willdepend on the nature and extent of the disease's effects, and can bedecided according to the judgment of a practitioner and each patient'scircumstances.

Typically, a composition according to the invention may be provided inan appropriate dispenser, such as a pump dispenser. A volume of thecomposition can be removed from the dispenser, placed into a hand, andadministered topically to a skin area in need of treatment. For example,a volume containing an effective amount of a composition of theinvention can be rubbed onto and/or into an area of a skin in need oftreatment. The composition may be administered at least once a day,twice a day, three times a day, once every other day, twice a week, oncea week, once every other week, or as needed.

The invention will be further and more specifically described by thefollowing examples. Examples, however, are included for illustrationpurposes, not for limitation.

EXAMPLES Example 1. Exemplary Compositions

Table 1 shows exemplary compositions containing a mixture of variousmolecular weights of sodium hyaluronate useful for the purposes of theinvention.

The ratios of the molecular weights of sodium hyaluronate recited inTable 1 are considered optimal for the intended utility of a compositionaccording to the invention.

TABLE 1 <0.01 0.01-0.45 0.45-1.65 1.65-4.0 >4.0 Wt. % MDa MDa MDa MDaMDa <0.001 E E 0.001 E E 0.01 E E 0.1 E E 1 E E 5 E E 50 E 95 E 99 99.999.99 99.999 >99.999E denotes effective, or acceptable for the purposes of the invention

Example 2. Exemplary Formulations

Table 2 shows exemplary formulations containing sodium hyaluronate andone or more other components (e.g., excipients). The exemplaryformulations may be prepared according to the methods as described inthe manufacturing processes above.

TABLE 2 Exemplary formulations Weight/weight percentages are shown.Micona- Cerimide/ Clinda- Acyclo- Clotri- zole NaHA NaHa mycin BPO virmazole NaHA Cotico NaHa Component A B C D E F G H I J 0.5M MW Sodium0.005 0.005 0.005 0.01 0.005 0.01 0.005 0.01 0.005 0.02 Hyaloranate 1.6MMW Sodium 0.01 0.01 0.01 0.02 0.01 0.02 0.01 0.02 0.01 0.04 Hyaloranate2.2M MW Sodium 0.085 0.085 0.085 0.17 0.085 0.17 0.085 0.17 0.085 0.34Hyaloranate Methylparaben — 0.2 0.2 0.2 — — — 0.2 — 0.2 Benzoyl Peroxide— — — 5.0 — — — — — White Petrolatum 82.0 — — — — 82.0 — 81.48 —Polyethylene Glycol 400 — — — 5.5 — 40.8 — — — — Propylparaben — 0.020.02 — — — 0.02 — 0.02 Castor Oil — — 0.9 — — — — — — Zinc Oxide 15.0 —— — — 15.0 — — — Carbomer 940 — 0.6 — 0.3 — — — 0.4 — 0.3 BetamethasoneValerate — — — — — — — 0.12 — Thixcin R 3.0 — — — — 3.0 — — — Cerimide 3— — 1.0 — — — — — — Cetyl Alcohol — — — 1.0 — — — — — Clotrimazole — — —— — 0.75 — — — Carbomer 141 — — 0.5 — — — — — — Dimethicone — — 0.9 — —— — — — Glycerin — 0.02 3.0 — — — — — — Mineral Oil — — — — — — — 18.3 —Glyceryl Sterarate — — — 3.0 — — — — — Butylated Hydroxytoluene 0.025 —— — — 0.025 — — — Polyethylene Glycol 3350 — — — — 29.0 — — — —Cholesterol — — 0.5 — — — — — — Acyclovir — — — — 5.0 — — — — Fragrance0.375 — 0.2 0.4 — 0.4 — — — Cerimide 1 — — 0.002 — — — — — — PurifiedWater — 98.83 91.78 76.2 81.2 — — 98.95 — 98.95 Clindamycin Phosphate —— — 1.0 — — — — — — Polyethylene Glycol 600 — — — 5.0 — — — — —Miconazole Nitrate 0.25 — — — — — — — — Propylene Glycol — — — 15.7 —25.0 — — — — Trolaminie — 0.23 — — — — 0.23 — 0.23 Sodium Hydroxyde 1.0M— — — q.s. — — — — — — Isoproyl Myrisate — — — 4.3 — — — — — Cerimide6-II — — 0.5 — — — — — Phytosphingosine — — 0.5 — — — — —

Example 3. Treatment of Dry and Scaly Skin

An exemplary hyaluronate composition according to the invention was usedto treat dry and scaly skin. The exemplary hyaluronate composition usedin this example contains about 0.1%, by mass, sodium hyaluronate havingmolecular weight substantially between about 1.6 million Daltons andabout 2.8 million Daltons, and at least about 99%, by mass, water, andone or more preservatives and thickening agents (for example, about 0.2%methylparaben NF, about 0.02% propylparaben NF, about 0.3% carbomer 940NF, about 0.15% trolamine NF).

An amount of the composition described above was provided in a suitablecontainer-closure system to each of a group of patients. Each patientdispensed the composition from the container-closure system provided andapplied the dispensed composition, two or three times daily, to areas ofskin that were dry and scaly. Subsequent to the application that tookplace over the course of at least three weeks, it was observed that theareas of skin that had been dry and scaly were noticeably improved(i.e., less dry and scaly) or cured (i.e., not dry or scaly at all).

Example 4. Treatment of Ichthyosis

A pediatric patient was suffering from scaling and dryness of the skin.A medical conclusion was drawn that the patient had ichthyosis. Aneffective amount of the exemplary composition as described in Example 3was administered topically to the patient b.i.d (twice a day), that is,by applying the composition to the areas of the patient's skin that wereaffected by scaling and dryness twice a day. Subsequent to the treatmentthat took place over the course of at least three weeks, the scaling anddryness had been greatly reduced.

Example 5. Treatment of Eczema

An approximately 14-year-old patient with eczema visited a universitydermatology clinic. The patient's medical history indicated that thepatient had suffered from eczema since the age of eight months. Aphysician at the clinic provided to the patient and the patient'smother, a registered nurse, an amount of the exemplary composition asdescribed in Example 3 in a suitable container-closure system. Thecomposition was applied topically at least once daily to the patientover the course of at least three weeks. It was subsequently observedthat the eczema was significantly ameliorated.

Example 6. Treatment of Very Dry and Rough Skin

A pediatric patient had very dry and sensitive skin. A physicianattending to the patient provided to the patient and the patient'smother an amount of the exemplary composition as described in Example 3in a suitable container-closure system. The composition was appliedtopically at least once daily to the patient over the course of at leastthree weeks. It was subsequently observed that the very dry skin wassignificantly ameliorated and that the previously rough dry skin nowappeared smooth.

Example 7. Treatment of Eczema in a Seven-Month-Old Patient

An approximately seven-month-old patient with eczema visited apediatrician. The patient had a family history of eczema; specifically,an older sibling and the child's father suffered from eczema. Thepatient was prescribed desoximatasone for topical administration to themost gravely affected areas. The results were not satisfactory.Subsequently, the pediatrician provided the patient's mother with anamount of the exemplary composition as described in Example 3 in asuitable container-closure system, for daily administration to thepatient. After two or more weeks of topical administration of thecomposition (during which time the aforementioned topical dexosimatasonewas not administered to the patient), patches of skin on the patient'shead, the tops of the patient's shoulders, the outside edges of thepatient's elbows, the patient's belly, the patient's thighs, and behindthe patient's knees that had previously been observed as flaky and scalynow appeared far less flaky and scaly or normal. Redness that hadpreviously been observed in those same areas was now observed to becompletely abated.

Example 8. Treatment of Fungal Infection

A liberal amount of a composition according to Column A or G in Table 2above is applied topically to an area of the skin of a human subject inneed of treatment for a fungal infection. It is observed that,subsequent to a regimen of daily topical administration of thecomposition for several days, the subject's fungal infection is abated.

Example 9. Treatment of Bacterial Infection

A liberal amount of a composition according to Column D in Table 2 aboveis applied topically to the skin of a human subject in need of treatmentfor a bacterial infection. It is observed that, subsequent to a regimenof daily topical administration of the composition for several days, thesubject's bacterial infection is abated.

Example 10. Treatment of Acne

A liberal amount of a composition according to Column E in Table 2 aboveis applied topically to the skin of a human subject in need of treatmentfor acne. It is observed that, subsequent to a regimen of daily topicaladministration of the composition for several days, the subject's acneis abated.

Example 11. Treatment of Viral Infection

A liberal amount of a composition according to Column F in Table 2 aboveis applied topically to the skin of a human subject in need of treatmentfor a viral infection of the integument. It is observed that, subsequentto a regimen of daily topical administration of the composition forseveral days, the subject's viral infection is abated.

Example 12. Treatment of Skin Disorders

A liberal amount of a composition according to any of the columns listedin Table 2 (for example, column B, C, H, I, or J) is applied topicallyto the skin of a human subject in need of treatment for eczema,dermatitis, atopic dermatitis, xerosis, psoriasis, inflammation, and/ordiaper rash. It is observed that, subsequent to a regimen of dailytopical administration of the composition for several days, thesubject's eczema, dermatitis, atopic dermatitis, xerosis, psoriasis,inflammation, and/or diaper rash is abated.

EQUIVALENTS

The foregoing has been a description of certain non-limiting embodimentsof the invention. Those skilled in the art will recognize, or be able toascertain using no more than routine experimentation, many equivalentsto the specific embodiments of the invention described herein. Those ofordinary skill in the art will appreciate that various changes andmodifications to this description may be made without departing from thespirit or scope of the present invention, as defined in the followingclaims.

In the claims articles such as “a,”, “an” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention also includes embodiments in which more than one, or all ofthe group members are present in, employed in, or otherwise relevant toa given product or process. Furthermore, it is to be understood that theinvention encompasses all variations, combinations, and permutations inwhich one or more limitations, elements, clauses, descriptive terms,etc., from one or more of the claims or from relevant portions of thedescription is introduced into another claim. For example, any claimthat is dependent on another claim can be modified to include one ormore limitations found in any other claim that is dependent on the samebase claim. Furthermore, where the claims recite a composition, it is tobe understood that methods of using the composition for any of thepurposes disclosed herein are included, and methods of making thecomposition according to any of the methods of making disclosed hereinor other methods known in the art are included, unless otherwiseindicated or unless it would be evident to one of ordinary skill in theart that a contradiction or inconsistency would arise. In addition, theinvention encompasses compositions made according to any of the methodsfor preparing compositions disclosed herein.

Where elements are presented as lists, e.g., in Markush group format, itis to be understood that each subgroup of the elements is alsodisclosed, and any element(s) can be removed from the group. It is alsonoted that the term “comprising” is intended to be open and permits theinclusion of additional elements or steps. It should be understood that,in general, where the invention, or aspects of the invention, is/arereferred to as comprising particular elements, features, steps, etc.,certain embodiments of the invention or aspects of the inventionconsist, or consist essentially of, such elements, features, steps, etc.For purposes of simplicity those embodiments have not been specificallyset forth in haec verba herein. Thus for each embodiment of theinvention that comprises one or more elements, features, steps, etc.,the invention also provides embodiments that consist or consistessentially of those elements, features, steps, etc.

Where ranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and/or the understanding of one of ordinary skill in the art,values that are expressed as ranges can assume any specific value withinthe stated ranges in different embodiments of the invention, to thetenth of the unit of the lower limit of the range, unless the contextclearly dictates otherwise. It is also to be understood that unlessotherwise indicated or otherwise evident from the context and/or theunderstanding of one of ordinary skill in the art, values expressed asranges can assume any subrange within the given range, wherein theendpoints of the subrange are expressed to the same degree of accuracyas the tenth of the unit of the lower limit of the range.

In addition, it is to be understood that any particular embodiment ofthe present invention may be explicitly excluded from any one or more ofthe claims. Any embodiment, element, feature, application, or aspect ofthe compositions and/or methods of the invention can be excluded fromany one or more claims. For purposes of brevity, all of the embodimentsin which one or more elements, features, purposes, or aspects isexcluded are not set forth explicitly herein.

INCORPORATION OF REFERENCES

All publications and patent documents cited in this application areincorporated by reference in their entirety to the same extent as if thecontents of each individual publication or patent document wereincorporated herein.

What is claimed is:
 1. A composition suitable for topical administrationto a mammalian subject, the composition comprising, by mass, from about0.05% to about 5% sodium hyaluronate and a pharmaceutically acceptableexcipient, wherein from about 0.001 wt % to about 5 wt % of the sodiumhyaluronate in the composition has a molecular weight ranging betweenabout 0.01 megadaltons and about 0.4 megadaltons; and wherein thepharmaceutically acceptable excipient is predominantly in the liquidphase at ambient temperature.
 2. The composition of claim 1, whereinfrom about 0.001 wt % to about 5 wt % of the sodium hyaluronate in thecomposition has a molecular weight ranging between about 0.5 megadaltonsand about 1.6 megadaltons.
 3. The composition of claim 2, wherein fromabout 50 wt % to about 95 wt % of the sodium hyaluronate in thecomposition has a molecular weight ranging between about 1.7 megadaltonsand about 4.0 megadaltons.
 4. The composition according to claim 1,wherein the pharmaceutically acceptable excipient is selected from thegroup consisting of water, an alcohol, an oil, glycerin, polyethyleneglycol, lanolin, petrolatum, wax, and poloxamer.
 5. The compositionaccording to claim 4, wherein the pharmaceutically acceptable excipientis alcohol selected from the group consisting of ethanol, benzylalcohol, isopropyl alcohol, octyldodecanol, cetostearyl alcohol, andlanolin alcohol.
 6. The composition according to claim 4, wherein thepharmaceutically acceptable excipient is oil selected from the groupconsisting of almond oil, castor oil, corn oil, cottonseed oil, lightmineral oil, mineral oil, olive oil, peanut oil, polyoxyl 35 castor oil,sesame oil, soybean oil, and sunflower oil.
 7. The composition accordingto claim 4, wherein the pharmaceutically acceptable excipient is water.8. The composition of claim 7, wherein the ratio of the mass of water tothe total mass of the composition ranges from about 60% to about 99.9%.9. The composition according to claim 7, wherein the ratio of the massof water to the total mass of the composition ranges from about 90.0% toabout 99.9%.
 10. The composition according to claim 7, wherein the ratioof the mass of water to the total mass of the composition ranges fromabout 92.5% to about 99.8%.
 11. The composition according to claim 7,wherein the ratio of the mass of water to the total mass of thecomposition ranges from about 95.0% to about 99.7%.
 12. The compositionaccording to claim 7, wherein the ratio of the mass of water to thetotal mass of the composition ranges from about 97.5% to about 99.6%.13. The composition according to claim 7, wherein the ratio of the massof water to the total mass of the composition ranges from about 98.5% toabout 99.5%.
 14. The composition according to claim 7, wherein the ratioof the mass of water to the total mass of the composition ranges fromabout 99.0% to about 99.4%.
 15. The composition according to claim 7,wherein the ratio of the mass of water to the total mass of thecomposition ranges from about 99.2% to about 99.3%.
 16. The compositionaccording to claim 5, wherein the ratio of the mass of water to thetotal mass of the composition is about 99.235%.
 17. The composition ofclaim 1, wherein the composition further comprises an antifungal agent.18. The composition according to claim 17, wherein the antifungal agentis selected from the group consisting of clioquinol, haloprogin,miconazole nitrate, povidone-iodine, tolnaftate, ketoconazole,undecylenic acid, butoconazole and clotrimazole.
 19. The compositionaccording to claim 18, wherein the antifungal agent is clotrimazole. 20.The composition according to claim 1, wherein the composition furthercomprises an antibiotic.